The broad goal of this proposal, that continues NCNPDDG grant CA52955, is to discover marine natural product leads for cancer chemotherapy. We seek structures from microorganisms and cultured microorganisms that will be useful against solid tumors for which there are few effective anti-cancer drug leads. The overall aims are: (a) to show that primary screens aimed at novel targets (oncogene products, tumor suppressor gene products, proteins involved in signal transduction, cell cycle regulation, angiogenesis and apoptosis) will guide the fractionation of natural product mixtures and identify active pure compounds. (b) To demonstrate that murine macro- and microorganisms will provide new anti-cancer leads. (c) To implement pre-fractionation strategies, which will provide an accelerated and more efficient paradigm for the identification of novel, active natural products. (d) To identify compounds in the primary and secondary screens, which act through novel mechanisms. (e) To employ in vivo PK, PD and efficacy studies (subcutaneous or orthotopic human tumor xenografts in nude mice and/or hollow fiber assays) to identify compounds with potential utility against important human solid tumors such as breast, colon, lung, ovarian and prostate. The strategy is to unite novel marine chemistry with unique assays based on new understanding in the molecular biology of cancer. The assays focus on a number of cancer relevant targets associated with the cell cycle, signal transduction, angiogenesis or apoptosis. The primary screens will be employed to examine library compounds and extracts of shallow and deep water murine organisms include: (a) sponges, (b) tunicates, (c) algae, (d) corals, (e) wild cyanophytes, (f) sponges with large populations of cyanophytes, (g) various cultured microalga, (h) cultured actinomycetes, and (i) cultured sponge-derived Gram negative bacteria. Active substances will be isolated, their structures established, and synthetic analogs and derivatives will be prepared for lead optimization. The program design has been effective as one marine natural product compound family of our NCDDG is the subject of a clinical trial scheduled for May 2000. Two other classes are seeds for further advanced development work. The project participants have a strong record of collaborative research and represent different institutions and distinct scientific disciplines: Cancer Biology and Medicinal Chemistry (Novartis Institute of Biomedical Research (NIBR) led by Dr. K.W. Bair; Marine Bioorganic Chemistry (University of California, Santa Cruz (UCSC) led by Dr. P. Crews, continuing as the overall PI; Marine Pharmaceutical Chemistry (Oregon State University (OSU), led by Dr. W.H. Gerwich and Marine Bioorganic Chemistry and Oceanography (Harbor Branch Oceanographic Institution (HBOI) led by Dr. A.E. Wright.